U.S. Pat. No. 4,199,574 describes a broad class of 6- and 2, 6-substituted purine derivatives containing an acyclic side chain (particularly hydroxyethoxymethyl) in the 9 position that were found to have antiviral activity against various classes of DNA viruses, particularly against herpes viruses such as herpes simplex. Among these derivatives, 9-(2-hydroxyethoxymethyl) guanine (generically known as acyclovir) has been found to have particularly good activity against herpes simplex viruses.
It is also known that a related class of purine derivatives characterized by the presence of a hydrogen atom in the 6 position of the purine nucleus is converted in vivo by the action of the molybdo-flavo-protein enzymes xanthine oxidase/dehydrogenase or aldehyde oxidase into the corresponding 6 hydroxypurine compound acyclovir. The 6-hydrogen compounds are disclosed in U.S. Pat. No. 5,059,604, issued Oct. 22, 1991 to Krenitsky and Beauchamp.
Another compound that is known to be useful for treating the viruses in the herpes simplex family is a compound called famciclovir chemically known as 2-[2-(2-amino-9H-purin-9-yl)ethyl]-1,3-propanediol diacetate. This compound is a prodrug of the antiviral agent penciclovir, which is the corresponding analog of famciclovir where there is a hydroxy at the 6 position in the purine ring instead of a hydrogen. The chemical name of penciclovir is 9-(4-hydroxy-3-hydroxymethyl-1-butyl)guanine. These and related compounds are described in U.S. Pat. Nos. 5,246,937 issued Sep. 21, 1993; 5,250,688 issued Oct. 5, 1993; and 5,075,445 issued Dec. 24, 1991.
The Food and Drug Administration (FDA) currently approves acyclovir and penciclovir for the treatment of vesicle outbreaks of HSV-I and HSV-II. Famciclovir is FDA approved for the treatment of the vesicle outbreak phase of herpes zoster. Such treatment requires blood levels between 0.5 microgram/milliliter (ugm/ml) and 1.0 ugm/ml for acyclovir and similar levels for famciclovir. The currently recognized oral doses required to reach this blood level for an adequate amount of time (which varies according to the virus being treated and is based upon the effective half-life of the drug) for reasonable therapeutic effect are as follows:
1. Famvir.RTM. brand famciclovir is only approved for use against Zoster at the oral doses of 500 mg three times per day. The absorption is linear in this dose range.
2. Zovirax.RTM. brand acyclovir is approved for several different uses against several different presentations of herpes viruses at oral doses that range between 200 mg three times per day and 800 mg 5 times per day. Because the absorption of acyclovir is non-linear in this dose range Burroughs-Wellcome, the manufacturer, has discouraged the use of higher doses because it believes little more can be absorbed with doses higher than the maximum dose of 800 mg 5 times per day, which in most patients gives a blood level near 1 umg/ml.
Autoimmune disorders are conditions in which the body's immune system produces antibodies to the body's own tissues (i.e., endogenous antigens). This attack on the body is the reason for the names autoimmune and autoantibody. Although, much is known about these diseases, the etiology of all of them is unknown as is the relationship between the various autoimmune disease conditions. It is known that in the most severe cases there is demonstrable antibody to otherwise apparently normal body tissue (i.e., autoantigens). However, there is a large spectrum of autoimmune-associated conditions that frequently occur in patients without demonstrable circulating autoantibodies. These include the myofascial pain syndrome, the irritable bowel syndrome, interstitial cystitis, etc. It is not known to current medical science whether these autoimmune-associated disorders are milder expressions of the same disease processes or totally separate entities. While it is assumed by many researchers in this field that there are causative agents for these conditions, such agents have not heretofore been identified.
At least four possible mechanisms are recognized for developing an immune response to auto-antigens. These are briefly discussed in The Merck Manual of Diagnosis and Therapy, Sixteenth Edition, Robert Berkow, M.D., Editor-in-Chief, 1992, Merck Research Laboratories, chap. 20. Many diseases that are thought to belong to this family of disorders are set forth at p. 340 of the Merck Manual. Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and systemic sclerosis (scleroderma, old name) are major diseases in this category. In the population afflicted with autoimmune disorders there is autoimmune inflammation, tissue destruction and often a very high level of pain. Frequently these signs and symptoms are so debilitating that a subject is so overcome that he or she can't function normally. Drugs for treating autoimmune diseases such as rheumatoid arthritis are set forth in The Medical Letter on Drugs and Therapeutics, vol. 36 (Issue 935), November 11, 1994. All of the current treatments such as non-steroidal anti-inflammatory agents (NSAIDS), steroids, etc. work by directly interfering with and suppressing the body's immune response. They all are inadequate primarily because of the following problems:
1. The current therapies only slow and diminish but do not arrest the inflammatory process and the progression of the autoimmune disease(s). This is because if they were used in a manner to totally suppress the immune system, the result would be the same as AIDS.
2. They frequently have such severe life threatening side effects that their use must be curtailed in the patient with the most severe autoimmune disease. Thus, the patients who need treatment most critically cannot get adequate control of the autoimmune inflammation before the regimen must be curtailed to prevent serious injury or death from the toxic effects of the medications. The side effects of many recognized treatments are too severe for use in "mild" autoimmune disease(s), the cure is often more dangerous than the disease(s) in these circumstances.
In accordance with this invention, it has now been found, that by administering certain 2-amino purine derivatives (e.g., certain antiviral compounds) at very high dosages, the signs and symptoms, particularly inflammation, tissue destruction and the pain, associated with autoimmune disorders can be ameliorated to the point where a subject can continue functioning in a normal fashion and the tissue destruction is arrested with no dangerous side effects, though with acyclovir there may be severe discomfort.